Heart failure is a pathophysiological state in which the heart is unable to pump enough blood to meet the nutrition and oxygen requirement of metabolizing tissues or cells. It is a major complication in many heart diseases. Adults over the age of 40 have an estimated 21% lifetime risk of developing heart failure (Lloyd-Jones, D. M. et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation 106, 3068-72 (2002), a condition responsible for more hospitalizations than all forms of cancer combined (American Heart Association. Heart Disease and Stroke Statistics—2003 Update, (American Heart Association, Dallas, Tex., 2003)).
Heart failure is a general term that describes the final common pathway of many disease processes. The most common cause is coronary artery disease, which can lead to a myocardial infarction (heart attack), often resulting in death of cardiac cells. The heart must then perform the same work with fewer cells. Chronic obstructive coronary artery disease can also cause heart failure in the absence of myocardial infarction. Valve disease or high blood pressure can lead to heart failure by increasing the workload of the heart. Rarer causes of heart failure, which primarily involve cardiac muscle, are classed as cardiomyopathy (although this term is sometimes used more generally to cover any cause of heart failure). The best characterized are a group of single gene disorders of the sarcomere which cause “hypertrophic cardiomyopathy” (in fact, a misnomer as many patients have no hypertrophy). In contrast, all patients with “dilated cardiomyopathy” have dilated thin walled ventricles. The genetics of this condition have yet to be characterized, but in many cases non-genetic causes are responsible (e.g. infections, alcohol, chemotherapeutic agents). Where no readily identifiable cause is found, the diagnosis used is “idiopathic” dilated cardiomyopathy (generally a diagnosis of exclusion).
A variety of pathophysiological changes occur in the heart as heart failure develops. In response to increased work load in vivo, the heart frequently increases in size (cardiac hypertrophy) as cardiac muscle cells develop hypertrophy (i.e., an increase in cell size in the absence of cell division). At the cellular and molecular levels, cardiac hypertrophy is characterized by increased expression of contractile proteins and activation of various signaling pathways whose role in the pathophysiology of heart failure remains incompletely understood.
Current treatments for heart failure include pharmacological methods, devices such as the ventricular assist device (VAD), and heart and heart-lung transplantation. Pharmacological approaches include the use of inotropic agents (i.e., compounds that increase cardiac contractility), neurohumoral blockers (e.g., .beta.-blockers, angiotensin converting enzyme inhibitors), aldosterone antagonists, diuretics, and vasodilators. However, none of these agents is fully effective either alone or in combination. Availability of transplants is limited, and since many individuals suffering from heart failure are in poor health, they are frequently not good surgical candidates. For these reasons heart failure remains a major cause of morbidity and mortality, particularly in the developed world. In addition, as indicated above it can be difficult to determine the etiology of heart failure, thus impeding the development of more specific therapies. In addition, there is a lack of diagnostic techniques at the molecular level. Thus there is a need in the art for the discovery of additional diagnostic markers and pharmacological targets for the development of new therapeutic approaches. In addition, there is a need in the art for improved techniques for evaluating the severity of heart failure and its response to treatment. The present invention addresses the foregoing needs, among others.